Method for treatment of emphysema

ABSTRACT

Disclosed herein is a method for treatment of emphysema by reducing the volume of the pulmonary alveoli or alveolar sacs which have been anomalously expanded with destruction by emphysema. The method includes a step (a) of inserting a catheter into a bronchus or bronchiole, a step (b) of injecting through said catheter a film-forming agent into the respiratory region including the pulmonary alveoli or alveolar sacs, thereby forming a film on the inner wall of said respiratory region, and a step (c) of shrinking said pulmonary alveoli or alveolar sacs.

This application claims the benefit under 35 U.S.C. 119(e) ofprovisional Application No. 61/376825, filed Aug. 25, 2010.

BACKGROUND

1. Technical Field

The present invention relates to a method for treatment of emphysema. Inparticular, the present invention relates to a method for treatment ofemphysema by reducing the volume of the pulmonary alveoli or alveolarsacs which have been anomalously expanded with destruction by emphysema.

2. Description of the Related Art

Among a large group of pulmonary diseases that hinder normal respirationis chronic obstruction pulmonary disease (COPD) which brings about lungocclusion on account of at least one disease selected from asthma,emphysema, and chronic bronchitis. COPD frequently involves thesediseases at one time and makes it difficult to confirm in each casewhich one of them really causes the lung occlusion. A case is clinicallydiagnosed as COPD by constant decrease in expiration flow from the lungover several months, even more than two years for a case of chronicbronchitis. Two of the most critical states relating to COPD are chronicbronchitis and emphysema.

The emphysema denotes a state of anomalous expansion with destructionthat occurs in the respiratory bronchioles which permit gas exchange andthe tissue called alveolar parenchyma such as pulmonary alveoli,alveolar sac and the like. The alveolar parenchyma in its normal stateshrinks at the time of expiration, but the one suffering from emphysemadoes not recover itself after expansion by respiration. This inhibitsnormal expiration. Moreover, emphysema decreases the effective area andvascular bed (which denotes capillary vessels running point to point onthe surface of the pulmonary alveoli) of the pulmonary alveoli, therebyreducing the gas exchange capacity of the entire lung. In addition,emphysema involves inflammation that destroys elastin and collagen,thereby causing the lung to decrease in elasticity. The result is thatthe lung cannot keep stretching and expanding the respiratory tract, andthis permits the bronchia to deform easily. As the result, the bronchusis compressed to become thin by its surrounding air-filled pulmonaryalveoli as the lung shrinks at the time of expiration. This makes thelung expand excessively, preventing air from being discharged easily(see WO 2009/075106 A1, ST MARIANNA UNIVERSITY SCHOOL, MIYAZAWA TERUOMI,“STENT FOR TRATING CHRONIC OBSTRUCTIVE PULMONARY DISEASE”). For thisreason, a patient of emphysema purses up his lips to expire (seeJadranka Spahija et al., “Effects of Imposed Pursed-Lips Breathing onRespiratory Mechanics and Dyspanea at Rest and During Exercise in COPD”,Chest 2005; 128:640-650).

In Japan, there are about 50,000 patients with emphysema who arereceiving home oxygen therapy, and it is estimated that about threemillion people including those of mild case are liable to emphysema. Atpresent, the major method of therapy for emphysema is home oxygentherapy. Oxygen therapy is commonly used for the patient who cannot takein sufficient oxygen from air on account of his seriously damaged lungfunction. However, it merely relieves the patient's condition but it isnot an effective method of therapy. On the other hand, there are severalmethods of pharmacotherapy including: administration of bronchodilatorto open respiratory tracts in the lung, thereby alleviating breathingdifficulties; administration of steroid by inhalation or mouth, therebyalleviating inflammation in respiratory tracts; administration ofantibiotics to prevent or treat secondary infection; and administrationof expectorant to remove mucus from respiratory tracts (see Jan A. vanNoord et al., “Effects of Tiotropium With and Without Formoterol orAirflow Obstruction and Resting Hyperinflation in Patients With COPD”,Chest 2006; 129:509-517). All of these pharmacotherapies help controlemphysema and alleviate its symptom, but they are not necessarilyeffective. In addition, there are several methods of surgical treatmentwhich include lung reductive surgery which removes damaged parts fromthe lung, thereby allowing the normal parts of the lung to expand andlung transplantation. However, these methods impose a heavy burden onpatients and involved difficulties in securing the lung to besubstituted (see Ware J H, et al., “Cost effectiveness ofLung-Volume-Reduction Surgery for Patients with Severe Emphysema”, TheNew England Journal of Medicine 2003; 348:2092-2102; National EmphysemaTreatment Trial Research Group, “A Randomized Trial ComparingLung-Volume-Reduction Surgery with Medical Therapy for SevereEmphysema”, The New England Journal of Medicine 2003; 348:2059-2073).

If it is possible to carry out “LVR (Lung Volume Reduction)”noninvasively without thoracotomy, many patients will have the chance oftherapy. However, the current noninvasive therapy has a low successrate. For example, one of the noninvasive therapy which is expected toproduce the same effect as “LVRS (Lung Volume Reduction Surgery)” is anindwelling device in which a one-way valve that prevents the entry ofinspired gas into the lung end is left in the bronchus (see Alferness,Clifton A et al., Spiration, Inc., U.S. Pat. No. 6,258,100 B1). However,once left in the lung, it prevents access to any place beyond itsindwelling point (see Mark L. Mathis, PneumRx, Inc., U.S. Pat. No.7,549,984 B1).

It is known that there exists a passage for air flow called bypass,which is different from the main respiratory tract, in the damagedrespiratory bronchioles and alveolar parenchyma. Therefore, even throughthe above-mentioned device prevents air from flowing through the mainrespiratory tract by the device, air gets around the obstruction by thedevice to reach the damaged respiratory bronchioles and alveolarparenchyma. Consequently, the above-mentioned device cannot prevent theexpansion of the lung (see ALJURI NIKOLAI at al., PULMONX, US2006/0264772 A1).

There is provided, as another non-surgical method of reducing the lungvolume, a method which comprises collapsing a region of the lung andbonding a part of the collapsed region to another region of the lung andfurther promoting the growth of fiber in the bonded tissue or thevicinity thereof to realize LVR (see Edward P. Ingenito et al., Bistech,Inc., U.S. Pat. No. 6,682,520 B1). In this method, however, it needs acertain length of time for the lung parenchyma to be destroyed by thereaction of the living body. The U.S. Pat. No. 6,682,520 B1 furthermentions a method for carrying out LVR by means of a material containingthat part of the damaged lung tissue to which targeting therapy isapplied. This method needs the part for targeting therapy and also needsa process in which the material reacts with the damaged part (see Gong;Glen et al., PneumRx, Inc., U.S. Pat. No. 7,678,767 B1).

The foregoing suggests that there exists no effective method fortreatment of emphysema at present, in the relevant field of art.

SUMMARY

It is an object of the present invention to provide a method forreducing the volume of the pulmonary alveoli or alveolar sacs sufferingfrom emphysema.

According to one embodiment of the present invention, the method fortreatment of emphysema comprises (a) inserting a catheter into abronchus or bronchiole, (b) injecting through said catheter afilm-forming agent into the respiratory region including the pulmonaryalveoli or alveolar sacs, thereby forming a film on the inner wall ofsaid respiratory region, and (c) shrinking said pulmonary alveoli oralveolar sacs.

The method according to the present invention can reduce less-invasivelythe volume of the pulmonary alveoli or alveolar sacs suffering fromemphysema.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1C are schematic sectional views showing the sequentialsteps of the method according to the present invention.

FIGS. 2A to 2F are schematic sectional views showing the sequentialsteps of the preferred method according to the first embodiment of thepresent invention.

FIGS. 3A to 3E are schematic sectional views showing the sequentialsteps of the preferred method according to the second embodiment of thepresent invention.

FIGS. 4A to 4F are schematic sectional views showing the sequentialsteps of the preferred method according to the third embodiment of thepresent invention.

FIGS. 5A and 5B are schematic sectional views showing the step (a)according to the preferred embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention, the method for treatment ofemphysema comprises a step (a) of inserting a catheter into a bronchusor bronchiole, a step (b) of injecting through said catheter afilm-forming agent into the respiratory region including the pulmonaryalveoli or alveolar sacs, thereby forming a film on the inner wall ofsaid respiratory region, and a step (c) of shrinking said pulmonaryalveoli or alveolar sacs. Incidentally, the term “treatment” as used inthis specification implies any medical practice to heal, alleviate,reduce, restore, prevent, or improve emphysema, symptoms of emphysema,or any symptoms that follow emphysema.

The present invention produces the effect of efficiently removingstagnant air in pulmonary alveoli or alveolar sacs (also referred to asalveolar parenchyma hereinafter) suffering from emphysema, oralleviating or preventing the overexpansion of the lung which weakens apatient due to emphysema or occlusion of air-supply bronchi to maintainthe reduced volume by respiration. It also produces the effect ofrestoring the alveolar parenchyma suffering from emphysema to itsoriginal size or less, thereby suppressing or preventing the compressionor occlusion of the surrounding bronchi by the surrounding alveolarparenchyma. The method for treatment according to the present inventionemploys a catheter and does not need any surgical treatment, and thisimposes a less burden to a patient. In addition to the foregoing, thepresent invention produces the effect of forming a film on the innerwall of alveolar parenchyma suffering from emphysema, therebyalleviating and preventing the overexpansion of the lung to restore theelasticity of the alveolar parenchyma suffering from emphysema.

Generally, the normal lung has no bypass or a very small bypass betweenadjacent alveoli; however, alveolar parenchyma suffering from emphysemaoften has holes called bypass that connect neighboring pulmonary alveolito one another. This bypass permits air to enter when an attempt is madeto suck out air by inserting a catheter into the overexpanded alveolarparenchyma suffering from emphysema, and such an attempt fails toalleviate the overexpansion of the lung. According to the presentinvention, this difficulty is overcome by injecting a film-forming agentinto the respiratory region including the pulmonary alveoli or alveolarsacs, thereby forming a film on the inner wall of the respiratory regionand substantially closing the alveolar parenchyma suffering fromemphysema. The result is that no or little air leaks when air is suckedout from the alveolar parenchyma suffering from emphysema, and hence airin the closed system is removed completely and the volume of thealveolar parenchyma decreases readily, efficiently, and rapidly.

The invention will be described below in more detail with reference tothe accompanying drawings.

FIGS. 1A to 1C are schematic sectional views showing the sequentialsteps of the method according to the present invention. The methodaccording to the present invention comprises inserting the catheter 1into the bronchus or bronchiole 2 [step (a)], injecting through saidcatheter the film-forming agent 4 (14, 24, 6) into the respiratoryregion including the pulmonary alveoli or alveolar sacs 3, therebyforming the film 5 (16, 27) on the inner wall of said respiratory region[step (b)], and shrinking said pulmonary alveoli or alveolar sacs [step(c)] as shown in FIG. 1A. Each step will be described below in moredetail, but it is not limited to the following.

1. Step (a)

This step is intended to insert the catheter into the bronchus orbronchiole. To be more specific, this step is intended to insert thecatheter 1 into the bronchus or bronchiole 2 communicating with therespiratory region including the pulmonary alveoli or alveolar sacssuffering from emphysema (referred to as alveolar parenchyma sufferingfrom emphysema hereinafter) 3 as shown in FIGS. 1A, 2A, 3A and 4A.

The catheter used in this step is not specifically restricted; it willbe properly selected according to the diameter (or the number ofbranching) of the bronchus or bronchiole into which it is introduced. Tobe concrete, it may be selected from any known medical catheters for therespiratory system, circulatory system, and digestive system. Thecatheter is not specifically restricted in structure, and it may or maynot have a balloon. The one with a balloon is desirable because of easewith which it is inserted into the tract or its sealing ability. Also,the catheter is not restricted in the number of its lumens. The numberof lumens should be properly selected according to the number of agentsto be used in the steps (b) and (c), which will be described below inmore detail, and the presence or absence of the balloon.

The insertion of the catheter 1 into the alveolar parenchyma 3 sufferingfrom emphysema will be facilitated with the help of the sheath 31extending to the desired position, as shown in FIG. 5A. The sheath 31 isnot specifically restricted in structure, and it may or may not have aballoon. However, it should preferably have the balloon 31 a which canclose the bronchus or bronchiole. The balloon 31 a attached to thesheath 31 and the balloon 1 a attached to the catheter 1 may be placedat any position in the bronchus or bronchiole without specificrestrictions. The balloon 31 a attached to the sheath 31 shouldpreferably be placed in the bronchus, and the balloon 1 a attached tothe catheter 1 should preferably be placed near the terminal of thebronchus, particularly in the bronchiole. The closing of the bronchus orbronchiole with the balloon 31 a heightens the air tightness at the partaway from the sheath. This leads to the effective use of the catheterfor the treatment of alveolar parenchyma suffering from emphysema. Inaddition, the balloon 1 a and the balloon 31 a may be used to closedifferent positions in the bronchus or bronchiole. In this way it ispossible to easily and separately control the pressure in the spacebetween the balloon 1 a and the balloon 31 a (for example, the normalalveolar parenchyma) and the pressure at the periphery of the balloon 1a (for example, the alveolar parenchyma suffering from emphysema).

With the bronchus or bronchiole closed by the balloon 31 a, the space onthe proximal side of the balloon 31 a is given an adequate breathingpressure necessary for pulmonary ventilation and this permits efficientand safe treatment. Expansion and shrinkage of the balloon 31 a may beaccomplished in any way without specific restrictions; the mostconvenient way is by means of the three-way stopcock 34 attached to thebase end of the sheath 31.

The balloon 31 a attached to the sheath 31 keeps constant the pressurein the space beyond it, and this permits stable operation at the forwardend of the catheter 1. For example, when the bronchus or bronchiole isclosed by the balloon 31 a and the space beyond the sheath 31 isdecompressed, the wall of the bronchus or bronchiole tightly adheres tothe balloon 1 a attached to the catheter 1. Thus the balloon 1 aprevents air from flowing through the bypass into the space beyond thecatheter 1, thereby facilitating decompression in the space beyond thecatheter. This also produces the effect of keeping the pressure in thespace beyond the sheath 31 constantly lower than the pressure for druginjection when a drug is being injected at a constant pressure into thespace beyond the catheter 1. The result is an efficient drug delivery.No specific restrictions are imposed on the way of controlling thepressure at the forward end (periphery) of the sheath 31 or at theforward end (periphery) of catheter 1. One typical method for pressurecontrol is shown in FIG. 5B. The sheath 31 is provided with the sealingstopcock 32 at its base end, so that the catheter 1 is inserted into thesheath 31 through the sealing stopcock 32. This arrangement closes thealveolar parenchyma beyond the forward end (periphery) of the sheath 31and permits easy pressure control in that part. The sheath 31 is alsoprovided at its base end with the three-way stopcock 33 through whichthe gas 38 is introduced or sucked in order to control the pressure inthe alveolar parenchyma beyond the forward end (periphery) thereof. Thesame way as mentioned above is used to control the pressure at theforward end (periphery) of the catheter 1. That is, as shown in FIG. 5Bthe catheter 1 is provided with the sealing stopcock 35 at its base end.This arrangement closes the alveolar parenchyma beyond the forward end(periphery) of the catheter 1 and permits easy pressure control in thatpart. The catheter 1 is also provided at its base end with the three-waystopcock 36 through which the gas or liquid 39 is introduced or suckedin order to control the pressure in the alveolar parenchyma beyond theforward end (periphery) thereof. No specific restrictions are imposed onthe way of expanding or shrinking the balloon 1 a. One typical way is byusing the three-way stopcock 37 attached to the base end of the catheter1. In addition, the catheter 1 may have a lumen as a passage for theguide wire 40 which helps insertion of the catheter 1 to the desiredposition.

For example, the catheter 1 may be one which is provided with theballoon 1 a to close the bronchus. (This catheter has a lumen to delivera liquid through the openings close to and away from the desired part.)The catheter 1 may also be a PTCA catheter of OTW type which is used fortreatment of angiostenosis in the cardiovascular region. The cathetersmentioned above may be commercial ones include microcatheter (such asFINECROSS (registered trademark), made by TERUMO CORPORATION), which isintended to pass a guide wire through angiostensis in the cardiovascularregion, and PTCA catheter (such as Ryuj in Plus OTW (registeredtrademark), made by TERUMO CORPORATION). The foregoing catheter is sodesigned as to be inserted into the lumen of the bronchus through theworking lumen of the bronchoscope; however, catheter does notnecessarily need the bronchoscope so long as catheter can be arranged atany desired position. In addition, the catheter 1 or the balloon 1 a maybe expanded to any size in outside diameter without specificrestrictions; an adequate size may be selected according to the diameterof the bronchus or bronchiole 2. Specifically, the outside diameterafter expansion of the balloon 1 a should preferably be slightly largerthan the inside diameter of the bronchus or bronchiole 2 communicatingwith any alveolar sac (air saccule) or pulmonary alveoli tissue intowhich the catheter is inserted or which is to be covered. Moredesirably, the outside diameter (Y mm) after expansion of the balloon 1a should be about 1 to 2 times the inside diameter (X mm) of thebronchus or bronchiole 2. In this case, the catheter or balloon can bepressed against the bronchus or bronchiole which is formed from elasticsmooth muscles without serious damages. In addition, the catheter orballoon also improves the removing efficiency of the film-forming agent4 mentioned later in the case of being discharged from the respiratoryregion.

The catheter may be introduced into the bronchus or bronchiole 2, with aguide wire inserted into its lumen (for example, for liquid delivery) ofthe catheter. Operation in this manner permits the tip of the guide wireto be placed closer to the periphery than the tip of the catheter. Inthis way, it is possible to introduce the tip of the catheter to thetissue near the alveolar sac (air saccule) or pulmonary alveoli close tothe periphery at the bronchus or bronchiole 2. The guide wire for thispurpose will be selected from any known ones for medical treatment ofthe respiratory system, circulatory system, and digestive system. It mayhave an adequate outside diameter according to the size of the lumen ofthe catheter. An example of the guide wire (GW for short hereinafter) isRunthrough (registered trademark) (having an outside diameter of 0.014inches made by TERUMO CORPORATION) which is used for treatment of theheart blood vessel.

The tip of the guide wire or catheter should preferably be provided witha radiopaque material, which indicates the position of the tip of theguide wire and catheter projecting from the forward end of the endoscopeduring X ray fluoroscopy. In this way the guide wire and catheter can beintroduced to the respiratory region including the pulmonary alveoli oralveolar sac suffering from emphysema, which has previously located by Xray fluoroscopy or CT scanning. The guide wire is removed when X rayfluoroscopy reveals that the tip of the catheter has reached the desiredposition. The foregoing operation should preferably be carried out insuch a way that the tip of the guide wire is positioned closer to theperiphery than the tip of the catheter. In addition, the tip of thecatheter should preferably have a reticulate or perforated structure sothat it will not adhere to the inner wall of the respiratory regionincluding pulmonary alveoli and alveolar sacs.

2. Step (b)

This step is intended to inject through the catheter the film-formingagent into the respiratory region including pulmonary alveoli oralveolar sacs, thereby forming a film on the inner wall of therespiratory region. Thus, even though there exist a bypass (indicated bythe reference numeral 6 in FIG. 1A) in the alveolar parenchyma sufferingfrom emphysema, the film-forming agent entirely covers the inner wallincluding the bypass of the alveolar parenchyma suffering fromemphysema. As the result of this step, the alveolar parenchyma sufferingfrom emphysema is closed except for openings communicating with thebronchi or bronchioles (see FIG. 1B). Thus, the closed alveolarparenchyma suffering from emphysema permits little or no air leakagewhen it is shrunk in the subsequent step. This ensures removal of airfrom the closed space and efficiently reduces the volume of the alveolarparenchyma. In addition, the film formed in this manner restores theelasticity of the alveolar parenchyma suffering from emphysema, therebyalleviating or preventing the overexpansion of the lung. Incidentally,the term “respiratory region” as used in this specification is a genericone that implies the respiratory organ at the periphery beyond thebronchus including the respiratory bronchiole and two alveoli. Therespiratory region typically includes the bronchus, bronchiole, terminalbronchiole, respiratory bronchiole, alveolar duct, alveoli, alveolarsac, pulmonary veins, and pulmonary artery. It should preferably includethe respiratory bronchiole, alveolar duct, alveoli, alveolar sac, andpulmonary veins.

The film-forming agent is injected through the catheter into therespiratory region including the alveoli or alveolar sacs, especiallythe alveolar parenchyma suffering from emphysema. This step shouldpreferably be carried out by using the catheter 1 provided with theballoon 1 a in such a way that the balloon 1 a is expanded to close thebronchus or bronchiole 2 prior to injection of the film-forming agent 4,as shown in FIG. 2B. In other words, the method according to the presentinvention has the step (b) in which the bronchus or bronchiole is closedby expanding the balloon attached to the catheter before thefilm-forming agent is injected. This operation prevents the film-formingagent 4 from flowing backward toward the trachea (proximal side) fromthe bronchus or bronchiole 2 and permits the film-forming agent 4 toefficiently come into contact with the aimed alveolar parenchyma 3suffering from emphysema. Expansion of the balloon 1 a attached to thecatheter 1 may be accomplished by any known method without specificrestrictions. For example, this object may be achieved by using thesyringe or indeflator connected to the lumen for balloon expansionarranged at the base end of the catheter. The balloon may be expanded byfilling it with any material, such as air, contrast medium, andphysiologic saline containing contrast medium, which is not specificallyrestricted. A gas, especially carbon dioxide or oxygen, is desirable inview of complication such as pneumonia. It is safe even in the case ofleakage due to balloon damage. The balloon will be placed at anyposition unrestrictedly. For example, the balloon may be placed at theend of the catheter or at a position slightly close to the trachea(proximal side) and slightly away from the end of the catheter. In thecase where the tip of the catheter is in the bronchus, the balloonshould be attached to the catheter such that it does not go beyond thebranch close to the bronchus.

According to a preferred procedure, the film-forming agent should beinjected after air has been introduced into the respiratory regionthrough the catheter. Since there exist usually no or very few bypassesin the normal alveolar parenchyma as mentioned above, the air injectedinto the respiratory region fills the normal alveolar parenchyma andhence the film-forming agent injected subsequently hardly enters thealveolar parenchyma. The normal alveolar parenchyma which accounts for avery small portion is affected negligibly by injection of thefilm-forming agent because there exist only a few bypasses. By contrast,since the alveolar parenchyma suffering from emphysema has small holes,called bypasses, communicating with neighboring pulmonary alveoli, theair injected into the respiratory region leaks through the bypasses andthe film-forming agent which is injected subsequently easily enters thealveolar parenchyma suffering from emphysema. Consequently, theforegoing procedure permits the film-forming agent to be selectivelyinjected into the alveolar parenchyma suffering from emphysema which hasbypasses. The pressure for air injection is not specifically restrictedso long as air does not substantially damage the normal alveolarparenchyma and the alveolar parenchyma suffering from emphysema and airsufficiently fills the normal alveolar parenchyma. That the normalalveolar parenchyma has been filled with air is known from the increasedair injection pressure indicated by the pressure gauge at hand. Thus,air is injected according to the monitored air pressure, and ifinjection pressure rises, the speed of injection may be decreased or theinjection may be suspended.

After air injection into the respiratory region through the catheter,the film-forming agent is injected at a pressure equal to or differentfrom the air injection pressure. The injection pressure for thefilm-forming agent should preferably be substantially equal to the airinjection pressure, so that the pressure in the normal alveolarparenchyma substantially balances with the injection pressure of thefilm-forming agent. In this situation there is no possibility of thefilm-forming agent entering the normal alveolar parenchyma or airescaping from the normal alveolar parenchyma. By contrast, uponinjection, the film-forming agent enters the alveolar parenchymasuffering from emphysema selectively and efficiently because the airpressure in the alveolar parenchyma suffering from emphysema is lowerthan the injection pressure of the film-forming agent.

For this reason, it is desirable to inject air into the respiratorregion through the catheter and then inject the film-forming agent whilekeeping the same injection pressure.

During this operation, it is desirable to temporarily suspend thepulmonary ventilation and keep a constant pressure in the areasurrounding the object in order that the lung in the area surroundingthe object is not affected by pressure fluctuation. Such a constantpressure should preferably be lower than the pressure of air beinginjected through the catheter 1. For example, a desirable pressure maybe a continued positive pressure or the open atmospheric pressure. Theforegoing operation may be carried typically by closing the bronchus orbronchiole which is closer to the center than the aimed bronchus orbronchiole and then inserting the catheter 1 into the aimed bronchus orbronchiole while keeping the pressure constant. That part of thebronchus close to the center which is to be closed may be the centralbronchus; however, it should preferably be the main bronchus or a partthereof close to the periphery side so that the remaining parts cancontinue ventilation. Particularly, as shown in FIG. 5A, the sheath 31is arranged at a closer position than the catheter 1 to be inserted intothe alveolar parenchyma 3 suffering from emphysema. The pressure(Pressure 1) in the bronchus and bronchiole between the balloon 1 a andthe balloon 31 a (for example, the normal alveolar parenchyma) can bekept lower than the pressure (Pressure 2) of injection through thecatheter 1 (Pressure 1<Pressure 2). The former pressure shouldpreferably be a positive pressure or the open atmospheric pressure. Onthe other hand, closing the balloon 1 a attached to the catheter 1prevents the film-forming agent 4 from flowing backward into the trachea(proximal side) of the bronchus or bronchiole 2. This permits thefilm-forming agent 4 to efficiently come into contact with the aimedalveolar parenchyma 3 suffering from emphysema. Any method may be usedunrestrictedly to control the pressure (Pressure 1) in the bronchus andbronchiole between the balloon 1 a and the balloon 31 a (for example,the normal alveolar parenchyma) and the pressure (Pressure 2) forinjection through the catheter 1. According to a preferred example ofthe method as shown in FIG. 5B, the sheath 31 is provided with thesealing stopcock 32 at the base end thereof and the catheter 1 isinserted into the sheath 31 through the sealing stopcock 32. The sealingstopcock 32 closes the alveolar parenchyma beyond the tip (periphery)side of the sheath 31, and this permits an easy control of pressure inthat part. In addition, the sheath 31 is provided with the three-waystopcock 33 at its base end. This three-way stopcock 33 permits the gas38 to be introduced or discharged so that the pressure (Pressure 1) inthe bronchus and bronchiole (for example, the normal alveolarparenchyma) between the balloon 1 a and the balloon 31 a can becontrolled positive or at the open atmospheric pressure. The foregoingis also applied to control the pressure of injection through thecatheter 1. That is, the catheter 1 is provided with the sealingstopcock 35 at its base end as shown in FIG. 5B. The sealing stopcock 35permits the gas to fill selectively and easily the closed normalalveolar parenchyma. The catheter 1 may be provided with the three-waystopcock 36 at its base end, which helps to control the pressure(Pressure 2) of injection through the catheter 1 by introducing ordischarging the gas 39 through the three-way stopcock 36.

This step is intended to form film on the inner wall of the respiratorregion by injection of the film-forming agent into the respirator regionincluding the pulmonary alveoli or alveolar sacs. This object may beachieved by any method, without specific restrictions, such as (b-1) to(b-3), illustrated in the following.

(b-1): This method comprises injecting a solution of viscous polymer asthe film-forming agent into the respiratory region through the catheterand then removing by suction an excess of the solution of viscouspolymer;

(b-2): This method comprises injecting the film-forming agent (which isa material that cures upon reaction with water or divalent metal ions)into the respiratory region through the catheter and then removing bysuction the material after reaction with water or divalent metal ionspresent on the surface of the respiratory region; or (b-3): This methodcomprises injecting a polymeric electrolyte (A) into the respiratoryregion through the catheter, removing by suction an excess of thepolymeric electrolyte (A), thereby allowing the polymeric electrolyte(A) to form a film on the inner wall of the respiratory region,injecting a polymeric electrolyte (B) which is charged opposite to thepolymeric electrolyte (A) into the respiratory region through thecatheter, thereby allowing the polymeric electrolyte (B) to come intocontact with the polymeric electrolyte (A), and removing by suction anexcess of the polymeric electrolyte (B). This method may optionally hasan additional step of injecting the polymeric electrolyte (A) into therespiratory region through the catheter after removal of the polymericelectrolyte (B) by suction, and removing by suction an excess of thepolymeric electrolyte (A) (in this case, the polymeric electrolyte (A)and the polymeric electrolyte (B) serve as the film-forming agent).

The preferable methods (b-1) to (b-3) are described below in moredetail; however, the following does not aim to restrict the scope of thepresent invention.

2-1. Step (b-1)

This step, shown in FIGS. 2B and 2C, involves injecting through thecatheter 1 the solution of viscous polymer 4 as the film-forming agentinto the bronchus or bronchiole 2 and into the respiratory regionincluding the alveoli or alveolar sacs 3 (as shown in FIG. 2B) and thenremoving by suction an excess of the solution of viscous polymer 4 (asshown in FIG. 2C). Incidentally, at the time of injection of thesolution of viscous polymer or removal of an excess of the solution ofviscous polymer by suction, it is desirable to expand the balloon 1 a soas to seal the space between the catheter 1 and the bronchus orbronchiole 2. Sealing in this manner permits secure injection of thesolution of viscous polymer and secure removal of an excess of thesolution of viscous polymer by suction.

The solution of viscous polymer 4 mentioned above forms, on account ofits viscous property, a thin film 5 of the solution on the inner wall ofthe respiratory region 3 (or the alveolar parenchyma suffering fromemphysema in the illustrated case) after removal by suction of thesolution. In addition, the thus formed film 5 covers the bypass 6, evenif the bypass 6 might exist in the alveolar parenchyma 3 suffering fromemphysema, because the bypass is usually a small hole. As a result, thealveolar parenchyma 3 suffering from emphysema is closed except for theholes communicating with the bronchus (FIG. 2C). The foregoing step ofshrinking the alveolar parenchyma suffering from emphysema permits thealveolar parenchyma suffering from emphysema to shrink readily andefficiently in the subsequent step because there is no air leakagethrough the bypass 6.

Incidentally, the solution of viscous polymer 4 may be optionallyinjected and removed by suction repeatedly, so that the inner wall ofthe alveolar parenchyma suffering from emphysema is coated entirely andfirmly with the film 5. The resulting film securely restores elasticityof the alveolar parenchyma suffering from emphysema, thereby alleviatingand preventing more the overexpansion of the lung. Also, if the bypassexists, the film securely closes the bypass. Moreover, it is possible toeasily control the film thickness by repeating the above-mentioned step.Further, it is possible to inject air after an excess of the solutionhas been removed by suction, optionally. Air injection in this mannersmoothens the inner wall of the alveolar parenchyma suffering fromemphysema, thereby improving adhesion between the film and the innerwall, even in the case where suction to remove an excess of the solutionshrinks the alveolar parenchyma suffering from emphysema and roughensits inner wall, thereby deteriorating adhesion between the film and theinner wall.

The viscous polymer mentioned above denotes any polymer which exhibitsviscosity (adhesiveness) when applied to a tissue of living body, suchas the alveolar parenchyma. The viscous polymer is not specificallyrestricted so long as the viscous polymer sticks to the alveolarparenchyma and closes the bypass. The viscous polymer is selected fromthe following materials which are commonly used for medical treatment.In particular, there are provided starch, gum arabic, sodium alginate,propylene glycol alginate, carboxyvinyl polymer, carmellose sodium,xanthan gum, gellan gum, gelatin, hydrolyzed gelatin, polyacrylic acid,polyacrylate, partially neutralized polyacrylate, starch polyacrylate,polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyvinyl alcohol (PVA), methylcellulose (MC), carboxymethyl cellulose (CMC), carboxymethyl cellulosesodium, and the like. The above-mentioned viscous polymers may be usedalone or in combination with one another. Preferable among the forgoingviscous polymer are water-soluble polymers such as carboxyvinyl polymer,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, methyl cellulose, starch, sodium alginate,gelatin, and hydrolyzed gelatin. More preferable examples includestarch, sodium alginate, gelatin, and hydrolyzed gelatin. They readilyadhere (stick) to the tissue of the living body and hardly run down fromthe applied part. The film formed from these materials is highlyintegral with the alveolar parenchyma suffering from emphysema and hencehardly peels off after the alveolar parenchyma is shrunk in thesubsequent step.

The solution of viscous polymer may be prepared by using any solventlisted below which can dissolve or disperse the viscous polymer.Examples are water; dimethylsulfoxide, dimethylformamide; glycols suchas ethylene glycol, diethylene glycol, propylene glycol, triethyleneglycol, polyethylene glycol, and polypropylene glycol; and oils and fatssuch as olive oil, castor oil, squalane, and lanolin. The foregoingsolvents may be used alone or in combination with one another. Of theseexamples, water and dimethylsulfoxide are preferable, and water is moredesirable. They are excellent in safety.

The solution of viscous polymer may contain the viscous polymer in anyconcentration unrestrictedly; however, preferable concentrations are 0.5to 50 wt %. These concentrations are suitable for the solution ofviscous polymer to adequately adhere (stick) to the inner wall of thealveolar parenchyma.

The amount of the solution of viscous polymer to be introduced into thealveolar parenchyma suffering from emphysema is not specificallyrestricted so long as it is enough for the solution of viscous polymerto fill the alveolar parenchyma suffering from emphysema. For example,injection should be suspended when an increase in the injection pressureof the solution of viscous polymer is detected. Likewise, the amount ofan excess of the solution of viscous polymer to be removed by suctionafter introduction is not specifically restricted so long as the amountis substantially enough for removal from the alveolar parenchymasuffering from emphysema. Removal by suction should be suspended whenthe solution of viscous polymer cannot be sucked. Incidentally, thesolution of viscous polymer may be introduced and removed through eitherthe same lumen or the different lumens of the catheter, but using thesame lumen is desirable for easy operation.

The solution of viscous polymer which has been applied to the inner wallof the alveolar parenchyma suffering from emphysema may be held therefor an unrestricted period of time; however, duration of one to fiveminutes is desirable for the solution of viscous polymer to start curingand forming the film on the inner wall of the alveolar parenchymasuffering from emphysema.

As mentioned above, the inside of the alveolar parenchyma suffering fromemphysema is substantially closed except for openings communicating withthe bronchus or bronchiole. Therefore, the solution of viscous polymeras the film-forming agent is somewhat integral with the lumen of thealveolar parenchyma 3 suffering from emphysema when the solution ofviscous polymer is removed by suction. Hence, the alveolar parenchyma 3shrinks as the removal by suction proceeds.

2-2. Step (b-2)

This step, shown in FIGS. 3B and 3C, involves injecting through thecatheter 1 the film-forming agent, which is the material 14 capable ofcuring upon reaction with water or divalent metal ions, into therespiratory region 2 (FIG. 3B) and then allowing the material 14 toreact with water or divalent metal ions (such as calcium ions) 15present on the inner wall of the respiratory region (which is thealveolar parenchyma suffering from emphysema in the figures) 3.Incidentally, when the material 14 is injected, it is desirable toexpand the balloon 1 a and seal the gap between the catheter 1 and theinner wall of the bronchus or bronchiole 2 (FIG. 3C). In this way thematerial 14 can be securely injected into the respiratory region (whichis the alveolar parenchyma suffering from emphysema in the figures) 3without the material 14 flowing backward. The above-mentioned reactioncures the material 14 to form the film 16 on the surface of the alveolarparenchyma 3 suffering from emphysema (FIG. 3C). Incidentally, thatportion of the material 14 which does not come into contact with wateror divalent metal ions 15 present on the surface of the alveolarparenchyma 3 suffering from emphysema remains as such without reaction(curing) (see the enlarged part of FIG. 3C). The unreacted (uncured)portion of the material 14 is rapidly removed by suction in thesubsequent step (c), with the film 16 remaining (FIG. 3D). Incidentally,when the material 14 is removed by suction, it is desirable to expandthe balloon 1 a so as to seal the gap between the catheter 1 and theinner wall of the bronchus or bronchiole 2. In this way, it is possibleto securely remove the material 14 from the alveolar parenchyma 3suffering from emphysema without the material 14 flowing toward thebronchus. In addition, the film 16 is formed so as to cover the bypass6, even if the bypass 6 exists in the alveolar parenchyma 3 sufferingfrom emphysema, because the bypass is usually a small hole. As theresult of the foregoing step, the alveolar parenchyma 3 suffering fromemphysema is closed except for the holes communicating with the bronchus(FIG. 3D). The foregoing step permits the alveolar parenchyma sufferingfrom emphysema to shrink readily and efficiently in the subsequent stepof shrinking the alveolar parenchyma suffering from emphysema becausethere is no air leakage through the bypass 6.

The material 14 capable of curing upon reaction with water, which isused as the film-forming material, is not specifically restricted solong as the material 14 starts to react (cure) with water on the surfaceof the tissue such as alveolar parenchyma of the living body and thematerial 14 also closes bypasses which might exist. Its preferableexamples include various kinds of cyanoacrylate monomer as listed below,which form polycyanoacrylate upon reaction with water. In particular,the examples are Alkyl- and cycloalkyl-α-cyanoacrylate, such asmethyl-α-cyanoacrylate, ethyl-α-cyanoacrylate, propyl-α-cyanoacrylate,butyl-α-cyanoacrylate, cyclohexyl-α-cyanoacrylate,heptyl-α-cyanoacrylate, and octyl-α-cyanoacrylate; alkenyl- andcycloalkenyl-α-cyanoacrylate, such as allyl-α-cyanoacrylate,methallyl-α-cyanoacrylate, and cyclohexenyl-α-cyanoacrylate;alkynyl-α-cyanoacrylate, such as propargyl-α-cyanoacrylate;aryl-α-cyanoacrylate, such as phenyl-α-cyanoacrylate andtoluoyl-α-cyanoacrylate; hetero-atom-containingmethoxyethyl-α-cyanoacrylate, ethoxyethyl-α-cyanoacrylate, andfurfuryl-α-cyanoacrylate; and silicon-containingtrimethylsilylmethyl-α-cyanoacrylate,trimethylsilylethyl-α-cyanoacrylate,trimethylsilylpropyl-α-cyanoacrylate, anddimethylvinylsilylmethyl-α-cyanoacrylate. The foregoing α-cyanoacrylatecompounds may be used alone or in combination with one another.Preferable among these examples are cyclohexyl-α-cyanoacrylate,heptyl-α-cyanoacrylate, and octyl-α-cyanoacrylate. Because of the longester side chain of cyanoacrylate, the cyanoacrylate give rise to a softpolymerized product (cured layer) which permits the alveolar parenchyma(alveoli or alveolar sacs) suffering from emphysema to readily shrink inthe subsequent step (c).

The material 14 capable of curing upon reaction with water, which servesas the film-forming material, may contain a plasticizer in addition tothe cyanoacrylate monomer. The plasticizer makes the resulting filmflexible so that the alveolar parenchyma (alveoli or alveolar sacs)suffering from emphysema readily shrink in the subsequent step (c).

The material 14 capable of curing upon reaction with divalent metalions, which serves as the film-forming material, will form the film byreaction (for curing) with calcium ions present on the surface of thealveolar parenchyma suffering from emphysema. Or, injection of thematerial 14 may be preceded by injection of a solution containingdivalent metal ions into the respiratory region 2 through the catheter1. This additional step promotes film formation. The solution containingdivalent metal ions is not specifically restricted so long as it iscapable of reacting with the material 14 and closing the bypass whichmight exist. It should be properly selected according to the kind of thematerial 14. A typical example of the combination of the material 14 andthe solution containing divalent metal ions is a combination of alginicacid and a compound which yields divalent ions, such as calcium ions,magnesium ions, and barium ions in an aqueous solution. Such a compoundincludes, for example, calcium chloride, calcium hydrogen phosphate,calcium dihydrogen phosphate, calcium triphosphate, calcium sulfate,calcium hydroxide, magnesium chloride, and barium chloride. An aqueoussolution of alginic acid and a compound that forms calcium ions in thesolution are preferable. In this case, the alginic acid undergoescrosslinking reaction with the calcium compound, thereby forming a gelwhich efficiently forms a film on the inner wall of the alveolarparenchyma suffering from emphysema. Incidentally, the solutioncontaining divalent metal ions is injected and removed by suction in thesame way as the material 14.

The material 14 capable of curing by reaction with water or divalentmetal ions, which serves as the film-forming agent, may be introducedinto the alveolar parenchyma suffering from emphysema in anyunrestricted amount which is enough to fill the alveolar parenchymasuffering from emphysema. For example, injection of the material 14should be suspended as soon as an increase in injection pressure of thematerial 14 is detected.

The material 14 may be kept in contact with water in the alveolarparenchyma suffering from emphysema or divalent metal ions (for example,calcium ion) for any unrestricted period of time, preferably one to fiveminutes. This duration is enough for the material 14 to react completelywith water in the alveolar parenchyma suffering from emphysema ordivalent metal ions. It is desirable to previously observe how thereaction proceeds when the film-forming agent 14 is dropped onto a slideglass at the same time of operation in the living body and then water isdropped onto the film-forming agent 14. The water droplets simulatewater present on the surface of the alveolar parenchyma suffering fromemphysema or divalent metal ions 15. The foregoing procedure reveals thereaction between the film-forming agent 14 and water or divalent metalions 15 that proceeds in the living body. It also easily and accuratelyprovides reaction state necessary to easily control the length of timefor the film-forming agent to be in contact with the inner wall of thealveolar parenchyma. Even though there exist the bypass 6 in thealveolar parenchyma suffering from emphysema, the film-forming agent 14forms the film 16 upon contact with water present on the surface of thealveolar parenchyma suffering from emphysema or with divalent metal ions15, thereby closing the bypass 6. With the bypass 6 closed, it ispossible to efficiently remove by suction the film-forming agent 14which remains unreacted.

As mentioned above, the inside of the alveolar parenchyma suffering fromemphysema is substantially closed except for openings communicating withthe bronchus or bronchiole. Therefore, the film-forming agent 14 issomewhat integral with the lumen of the alveolar parenchyma 3 sufferingfrom emphysema when the film-forming agent 14 is removed, and hence thealveolar parenchyma 3 shrinks as the removal by suction proceeds.

2-3. Step (b-3)

This step, shown in FIGS. 4B to 4E, involves injecting through thecatheter 1 the polymeric electrolyte (A) 24 into the respiratory region2 (FIG. 4B) and then removing by suction an excess of the polymericelectrolyte (A) 24 (FIG. 4C). After removal by suction, the polymericelectrolyte (A) remains in the form of thin film 25 on the inner wall ofthe alveolar parenchyma 3 suffering from emphysema (FIG. 4C). Inaddition, the thus formed film 25 of the polymeric electrolyte (A) 24covers the bypass 6 which might exist in the alveolar parenchyma 3suffering from emphysema because the bypass is usually a small hole. Asthe result of the foregoing step, the polymeric electrolyte (A) 24 formsthe film 25 that covers the bypass 6. Incidentally, when the polymericelectrolyte (A) 24 is injected or removed by suction, it is desirable toexpand the balloon 1 a so as to seal the gap between the catheter 1 andthe inner wall of the bronchus or bronchiole 2 (FIG. 4B). In this waythe polymeric electrolyte (A) 24 can be securely injected into therespiratory region (the alveolar parenchyma suffering from emphysema inthe figures) 3 without it flowing backward and it can also be securelyremoved from the alveolar parenchyma 3 suffering from emphysema withoutit flowing into the bronchus.

Subsequently, the polymeric electrolyte (B) 26, which has electriccharges opposite to those of the polymeric electrolyte (A) 24, isinjected into the respiratory region 2 through the catheter 1, so thatit comes into contact with the film 25 of the polymeric electrolyte (A)24 (FIG. 4D). As the result of this procedure, the electric charges(such as positive charges) of the polymeric electrolyte (B) 26 reactwith the opposite electric charges (such as negative charges) of thepolymeric electrolyte (A) 24, thereby forming the ion complex film 27.Therefore, the ion complex film 27 remains on the inner wall of thealveolar parenchyma 3 suffering from emphysema after the polymericelectrolyte (B) 26 has been removed by suction (FIG. 4E). In addition,even in the case where the bypass 6 exists in the alveolar parenchyma 3suffering from emphysema, the polymeric electrolyte (A) 24 covering thebypass 6 as mentioned above reacts with the polymeric electrolyte (B)26, thereby forming the ion complex film 27. Consequently, the alveolarparenchyma 3 suffering from emphysema is closed except for the holecommunicating with the bronchus (FIG. 4E). Incidentally, when thepolymeric electrolyte (B) 26 is injected or removed by suction, it isdesirable to expand the balloon 1 a so as to seal the gap between thecatheter 1 and the inner wall of the bronchus or bronchiole 2 (FIG. 4E).In this way the polymeric electrolyte (B) 26 can be securely injectedinto the respiratory region (the alveolar parenchyma suffering fromemphysema in the figures) 3 without it flowing backward and it can alsobe securely removed from the alveolar parenchyma 3 suffering fromemphysema without it flowing into the bronchus.

The foregoing step may be carried out in such a way that the procedurefor injection and removal by suction of the polymeric electrolyte (A) isrepeated alternately and the procedure for injection and removal bysuction of the polymeric electrolyte (B) is repeated alternatelyaccording to need. For example, after the polymeric electrolyte (B) 26has been removed by suction, the polymeric electrolyte (A) is injectedinto the respiratory region through the catheter and then an excess ofthe polymeric electrolyte (A) is removed by suction (not shown). As theresult of this procedure, the electric charges (negative charges in theabove-mentioned example) of the polymeric electrolyte (B) 26 which werenot involved in formation of the ion complex film 27 react with theelectric charges (positive charges in the above-mentioned example) ofthe polymeric electrolyte (A) injected later, so that an additional filmis formed. This procedure, therefore, gives a firmer film and permitsthe alveolar parenchyma suffering from emphysema to shrink securely andreadily in the subsequent step. It also securely closes the bypass whichmight exist. Repetition of that procedure permits easy control of thethickness of the film. Incidentally, the polymeric electrolyte (A) andthe polymeric electrolyte (B), which are used in this step, serve as thefilm-forming agent according to the present invention.

The polymeric electrolyte (A) 24 and the polymeric electrolyte (B) 26are acceptable so long as they have mutually opposite charges. Forexample, if the polymeric electrolyte (A) 24 is one which has negativecharges, the polymeric electrolyte (B) 26 should be one which haspositive charges. If the polymeric electrolyte (A) 24 is one which haspositive charges, the polymeric electrolyte (B) 26 should be one whichhas negative charges

The polymeric electrolyte having negative charges is not specificallyrestricted so long as it has at least one, preferably two or more,anionic groups. It includes, for example, polyamino acid, artificialsynthetic polypeptide, polysaccharides such as heparin, hyaluronic acid,chondroitin, pectin, agarose, glycosaminoglycan, cellulose, and starch,and artificial synthetic polysaccharides. The synthetic polymer may haveany weight-average molecular weight unrestrictedly, ranging from about10,000 to 1,000,000, preferably from about 100,000 to 700,000, and morepreferably from about 200,000 to 500,000. The polymeric electrolytesmentioned above may be used alone or in combination with one another.Preferable among the examples listed above are heparin, hyaluronic acid,chondroitin, pectin, agarose, and glycosaminoglycan, with heparin,hyaluronic acid being more preferable.

The polymeric electrolyte having negative charges may also be one whichis obtained by polymerization of monomers having negative charges. Themonomers having negative charges are those which have at least onefunctional group selected from sulfo group (—SO₃H), carboxyl group(—COOH), phosphonic acid group (—PO₃H₂), and the like, but is notlimited thereto.

Unrestricted examples of the monomer having sulfo group (—SO₃H) includevinylsulfonic acid (ethylene sulfonic acid), 2-propenesulfonic acid,3-butenesulfonic acid, 4-pentenesulfonic acid, sulfomethyl(meth)acrylate, 2-sulfoethyl (meth)acrylate, 3-sulfopropyl(meth)acrylate, 2-methyl-3-sulfopropyl (meth)acrylate, 4-sulfobutyl(meth)acrylate, N-(2-sulfoethyl) 4-sulfobutyl (meth)acrylate,2-(meth)acrylamide-2-methylpropanesulfonic acid, N-(2-sulfoethyl)(meth)acrylamide, N-(1-methyl-2-sulfoethyl) (meth)acrylamide,N-(2-methyl-3-sulfopropyl) (meth)acrylamide, N-(4-sulfobutyl)(meth)acrylamide, 10-sulfodecyl (meth)acrylate, styrenesulfonic acid,(meth) allyl sulfonate, allylsulfonic acid,3-(meth)acryloxy-2-hydroxypropyl sulfonate,3-(meth)acryloxy-2-hydroxypropyl sulfophenyl ether,3-(meth)acryloxy-2-hydroxypropyloxysulfobenzoate,4-(meth)acryloxybutylsulfonate, (meth)acrylamide methylsulfonic acid,(meth)acrylamide ethylsulfonic acid, and 2-methylpropanesulfonic acid(meth)acrylamide.

Unrestricted examples of the monomer having carboxyl group include(meth) acrylic acid, maleic acid, fumaric acid, glutaconic acid,itaconic acid, crotonic acid, sorbic acid, cinnamic acid,N-(meth)acryloylglycine, N-(meth)acryloylaspartic acid,N-(meth)acryloyl-5-aminosalicylic acid, 2-(meth)acryloyloxyethylhydrogensuccinate, 2-(meth)acryloyloxyethylhydrogen phthalate,2-(meth)acryloyloxyethylhydrogen maleate,6-(meth)acryloyloxyethylnaphthalene-1,2,6-tricarboxylic acid,O-(meth)acryloyltyrosine, N-(meth)acryloyltyrosine,N-(meth)acryloylphenylalanine, N-(meth)acryloyl-p-aminobenzoic acid,N-(meth)acryloyl-o-aminobenzoic acid, p-vinylbenzoic acid,2-(meth)acryloyloxybenzoic acid, 3-(meth)acryloyloxybenzoic acid,4-(meth)acryloyloxybenzoic acid, N-(meth)acryloyl-5-aminosalicylic acid,and N-(meth)acryloyl-4-aminosalicylic acid.

Unrestricted examples of the monomer having phosphonic acid groupinclude phosphooxyethyl (meth)acrylate,3-(meth)acryloxypropyl-3-phosphonopropionate,3-(meth)acryloxypropylphosphonoacetate,4-(meth)acryloxybutyl-3-phosphonopropionate,4-(meth)acryloxybutylphosphonoacetate,5-(meth)acryloxypentyl-3-phosphonopropionate,5-(meth)acryloxypentylphosphonoacetate,6-(meth)acryloxyhexyl-3-phosphonopropionate,6-(meth)acryloxyhexylphosphonoacetate,10-(meth)acryloxydecyl-3-phosphonopropionate,10-(meth)acryloxydecylphosphonoacetate,2-(meth)acryloxyethyl-phenylphosphonate,2-(meth)acryloyloxyethylphosphonic acid,10-(meth)acryloyloxydecylphosphonic acid, andN-(meth)acryloyl-ω-aminopropylphosphonic acid.

The monomers mentioned above may be used alone or in combination withone another.

The polymeric electrolyte having positive charges is not specificallyrestricted so long as it has one or more than one cationic groups. Itincludes, for example, polyethyleneimine and an organic compound havingN,N-dimethylaminoalkyl group in its branched chain. The polymericelectrolyte mentioned above may have any weight-average molecular weightunrestrictedly, ranging preferably from about 10,000 to 1,000,000, andmore preferably from about 100,000 to 500,000. The polymericelectrolytes mentioned above may be used alone or in combination withone another. Preferable among the examples listed above arepoly(N,N-dimethylaminopropylacrylamide) having a weight-averagemolecular weight of about 10,000 to 1,000,000,poly(N,N-dimethylaminoethylacrylamide) having a weight-average molecularweight of about 10,000 to 1,000,000, and polyethyleneimine having aweight-average molecular weight of about 10,000 to 1,000,000. Morepreferable ones are poly(N,N-dimethylaminopropylacrylamide) having aweight-average molecular weight of about 10,000 to 500,000,poly(N,N-dimethylaminoethylacrylamide) having a weight-average molecularweight of about 10,000 to 500,000, and polyethyleneimine having aweight-average molecular weight of about 10,000 to 500,000 (especiallyabout 100,000).

The polymeric electrolyte having positive charges may be obtained bypolymerization of monomers having positive charges. The monomers havingpositive charges are not specifically restricted but they include thosewhich have at least one functional group selected from amino group(—NH₂), imino group (═NH, —NH—), imidazoyl group, and pyridyl group.

The monomers having amino group unrestrictedly include (meth)allylamine, aminoethyl (meth)acrylate, aminopropyl (meth)acrylate,dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate,methylethylaminoethyl (meth)acrylate, dimethylaminopropyl(meth)acrylate, dimethylaminostyrene, diethylaminostyrene,morpholinoethyl (meth)acrylate, and lysine.

The monomers having imino group unrestrictedly includeN-methylaminoethyl (meth)acrylate, N-ethylaminoethyl (meth)acrylate,N-t-butylaminoethyl (meth)acrylate, and ethyleneimine.

The monomers having imidazoyl group unrestrictedly include4-vinylimidazole, N-vinyl-2-ethylimidazole, andN-vinyl-2-methylimidazole.

The monomers having pyridyl group include 2-vinylpyridine,4-vinylpyridine, and 2-methyl-5-vinylpyridine.

The above-mentioned monomers may be used alone or in combination withone another.

Incidentally, the polymeric electrolyte (A) 24 and the polymericelectrolyte (B) 26 may be constructed of not only the above-mentionedmonomers having negative charges or positive charges but also any otherknown monomers as exemplified below which is not specificallyrestricted. Particularly, monomers having carboxyl groups in the form ofsalt such as sodium salt, potassium salt, and ammonium salt; Monomershaving sulfo groups in the form of monovalent metal salt, divalent metalsalt, ammonium salt, and organic amine salt; (poly)alkyleneglycoldi(meth)acrylates, such as triethylene glycol di(meth)acrylate,(poly)ethylene glycol di(meth)acrylate, polypropylene glycoldi(meth)acrylate, and (poly)ethyleneglycol (poly)propylene glycoldi(meth)acrylate; difunctional (meth)acrylates, such as hexanedioldi(meth)acrylate, trimethylolpropane tri(meth)acrylate, andtrimethylolpropane di(meth)acrylate; (poly)alkyleneglycol dimaleates,such as triethyleneglycol dimaleate and polyethyleneglycol dimaleate;esters of unsaturated monocarboxylic acids and alcohols having 1 to 4carbon atoms, such as methyl (meth)acrylate, ethyl (meth)acrylate,propyl (meth)acrylate, glycidyl (meth)acrylate, methyl crotonate, ethylcrotonate, and propyl crotonate; amides of unsaturated monocarboxylicacids and amines having 1 to 30 carbon atoms, such as methyl(meth)acrylamide; vinyl aromatics, such as styrene, α-methylstyrene,vinyltoluene, and p-methylstyrene; alkanediol mono(meth)acrylates, suchas 1,4-butanediol mono(meth)acrylate, 1,5-pentanediolmono(meth)acrylate, and 1,6-hexanediol mono(meth)acrylate; dienes, suchas butadiene, isoprene, 2-methyl-1,3-butadiene, and2-chloro-1,3-butadiene; unsaturated amides, such as (meth) acrylamide,(meth) acrylalkylamide, N-methylol (meth) acrylamide, and N,N-dimethyl(meth)acrylamide; unsaturated nitriles, such as (meth)acrylonitrile andα-chloroacrylonitrile; unsaturated esters, such as vinyl acetate andvinyl propionate; and unsaturated amines, such as aminoethyl(meth)acrylate, methylaminoethyl (meth)acrylate, dimethylaminoethyl(meth)acrylate, dimethylaminopropyl (meth)acrylate, dibutylaminoethyl(meth)acrylate, and vinylpyridine. These monomers may be used alone orin combination with one another. In the case where the polymericelectrolyte has constituents derived from additional monomers, theamount of the additional monomers is not specifically restricted so longas it is small enough not to adversely affect the monomers havingpositive charges or negative charges. It should preferably be 1 to 10 wt% in the total amount.

According to the present invention, the polymeric electrolyte (A) andthe polymeric electrolyte (B) have mutually opposite charges; therefore,the above-mentioned monomers should be properly selected for productionof the polymeric electrolyte (A) and polymeric electrolyte (B) so thatthe polymeric electrolyte (A) and polymeric electrolyte (B) are chargedoppositely.

The polymeric electrolytes according to the present invention may beproduced by any known unrestricted method for polymerization. It isusually produced from the above-mentioned monomers by polymerizationwith the help of a polymerization initiator. Polymerization procedure ofthe monomers may be accomplished which is not specifically restricted inany way, such as solution polymerization and bulk polymerization. If thepolymeric electrolytes according to the present invention are blockcopolymers or graft copolymers, they can be produced unrestrictedly byany of living polymerization, polymerization from macro monomers,polymerization with the help of a polymeric polymerization initiator,and polycondensation.

The polymeric electrolyte (A) or the polymeric electrolyte (B) may beinjected as such into the respirator region or may be used in the formof solution or dispersion in a proper solvent. The solvent for solutionor dispersion is not specifically restricted so long as it is capable ofdissolving or dispersing the polymeric electrolyte (A) or the polymericelectrolyte (B) and safe. Examples of the solvent include water,dimethylsulfoxide, dimethylformamide, glycols such as ethylene glycol,diethylene glycol, propylene glycol, triethylene glycol, polyethyleneglycol, and polypropylene glycol, and fats and oils such as olive oil,castor oil, squalane, and lanolin. The above-mentioned solvents may beused alone or in combination with one another. Preferable among theabove-mentioned solvents are water, dimethylsulfoxide anddimethylformamide, which are safe, and water is more desirable.

No specific restrictions are imposed on the concentrations of thepolymeric electrolyte (A) and the polymeric electrolyte (B) in thesolution or dispersion to be injected into the respiratory region. Apreferred concentration is 5 to 50 wt %. This concentration is desirablefor the solution or dispersion to readily and efficiently form the filmon the inner wall of the alveolar parenchyma suffering from emphysema.The polymeric electrolyte (A) and the polymeric electrolyte (B) may haveidentical or different concentrations in their solution or dispersion.

The polymeric electrolyte (A) and the polymeric electrolyte (B) may bemixed together in any ratio unrestrictedly. The mixing ratio shouldpreferably be from 1:0.1 to 1:5, more preferably from 1:0.5 to 1:2 (bymass). This mixing ratio is desirable for the polymeric electrolyte (A)and the polymeric electrolyte (B) to react with each other efficiently,thereby forming the ion complex film over the entire surface of theinner wall of the alveolar parenchyma suffering from emphysema.

The polymeric electrolyte (A) or the polymeric electrolyte (B) may beintroduced into the alveolar parenchyma suffering from emphysema in anyamount unrestrictedly so long as the polymeric electrolyte (A) and thepolymeric electrolyte (B) sufficiently fill the alveolar parenchymasuffering from emphysema. For example, injection of the polymericelectrolyte (A) or the polymeric electrolyte (B) should be suspended assoon as an increase in injection pressure of the polymeric electrolyte(A) or the polymeric electrolyte (B) is detected. Likewise, thepolymeric electrolyte (A) and the polymeric electrolyte (B) may beremoved by suction from the alveolar parenchyma suffering from emphysemain any amount unrestrictedly so long as they can be substantiallyremoved from the alveolar parenchyma suffering from emphysema. Forexample, after injection of the polymeric electrolyte (A) or thepolymeric electrolyte (B), removal of the excess polymeric electrolyte(A) or the polymeric electrolyte (B) should be suspended as soon as itbecomes impossible to continue suction. Incidentally, the polymericelectrolyte (A) or the polymeric electrolyte (B) may be injected andremoved through either the same lumen or the different lumens of thecatheter, but using the same lumen is desirable for easy operation. Thepolymeric electrolyte (A) 24 and the polymeric electrolyte (B) 26 may beinjected and removed once or preferably several times respectively, sothat they entirely cover the inner wall of the alveolar parenchymasuffering from emphysema.

Injection of the polymeric electrolyte (A) 24 and the polymericelectrolyte (B) 26 into the alveolar parenchyma suffering from emphysemamay be followed by injection of an adequate gas, so that the previouslyinjected polymeric electrolytes uniformly cover the surface of thealveolar parenchyma 3 suffering from emphysema. A desirable gas for thispurpose is one which is less viscous than the polymeric electrolytes, sothat it permits the polymeric electrolyte to form a uniform film on thesurface of the alveolar parenchyma. The gas may be selectedunrestrictedly from air, oxygen, carbon dioxide, carbon monoxide,nitrogen, helium, and argon.

The polymeric electrolyte (A) 24 and the polymeric electrolyte (B) 26may remain in contact with each other in the film 25 for anyunrestricted period of time. Duration of 1 to 10 minutes is desirablefor the polymeric electrolyte (A) 24 and the polymeric electrolyte (B)26 to react completely with each other.

After reaction is completed between the polymeric electrolyte (A) 24 andthe polymeric electrolyte (B) 26, the polymeric electrolyte (B) 26 isremoved by suction. Since the alveolar parenchyma suffering fromemphysema is closed except for the hole communicating with the bronchusor bronchiole, the polymeric electrolyte (B) 26 is removed somewhattogether with the lumen of the alveolar parenchyma 3 suffering fromemphysema. Thus the alveolar parenchyma 3 shrinks as the result ofremoval by suction.

The film-forming agents used in the above-mentioned steps (b-1) to (b-3)are slow in curing to form the film. Such steps (b-1) to (b-3) areparticularly desirable because the alveolar parenchyma suffering fromemphysema is kept shrunk until curing after the subsequent step (c).

3. Step (c)

This step is intended to shrink the alveolar parenchyma (pulmonaryalveoli or alveolar sacs) suffering from emphysema which had the filmformed on the inner wall thereof by the previous step (b). As the resultof this step, the alveolar parenchyma suffering from emphysema rapidlyshrinks, so that air remaining in the alveolar parenchyma suffering fromemphysema is efficiently removed. The film-forming agents used in theabove-mentioned steps (b-1) to (b-3) are slow to cure to form the filmand hence they complete film formation after shrinkage therefore theykeep the alveolar parenchyma suffering from emphysema shrunk andefficiently reduce the volume of the alveolar parenchyma and permit thepatient to maintain this reduced volume at the time of respiration. Thisalleviates and prevents the overexpansion of the lung due to emphysemaor occlusion of air-supply bronchi which weakens the patient. The resultis that the alveolar parenchyma suffering from emphysema can be madesmaller than its original size, and this alleviates and prevents thepressure and occlusion of the bronchi by the peripheral alveolarparenchyma. In addition, the above-mentioned steps (a) to (c) accordingto the present invention enable treatment through a catheter without theneed for surgical treatment, and this leads to a reduced burden on thepatient.

This step is designed to shrink the alveolar parenchyma (alveoli oralveolar sacs) suffering from emphysema in any unrestricted way. Forexample, one of the following steps (c-1) to (c-4) is desirable.

(c-1): This step involves filling through the catheter a reactive gasinto the alveoli or alveolar sacs, closing the bronchus or bronchiolewith an adequate closing means, and injecting an agent that absorbs saidreactive gas into the alveoli or alveolar sacs.

(c-2): This step, which employs a film-forming agent which forms afoam-like film, is designed to eliminate foams resulting from thefilm-forming agent or remove by suction the foam-like film-forming agentthrough the catheter, after the step (b) mentioned above.

(c-3): This step involves removing by suction through the catheter thegas remaining in the alveoli or alveolar sacs, and

(c-4): This step involves removing by suction the film-forming agentfrom the alveoli or alveolar sacs.

Incidentally, the step (c-4) also involves removing by suction thefilm-forming agent like the foregoing steps (b-1) to (b-3); therefore,the step (c-4) may be omitted if removing by suction is carried out inthe steps (b-1) to (b-3).

The following is a description of the preferred methods for carrying outthe steps (c-1) to (c-3); however, they are not intended to restrict thescope of the present invention.

3-1. Step (c-1)

This step, as shown in FIGS. 2D to 2F, involves injecting the reactivegas 7 into the respiratory region 2 through the catheter 1, therebyfilling the reactive gas 7 into the pulmonary alveoli or alveolar sacs(the alveolar parenchyma suffering from emphysema) 3. At the time offilling of the reactive gas 7, it is desirable to seal, by expanding theballoon 1 a, the gap between the catheter 1 and the inner wall of thebronchus or bronchiole 2 (FIG. 2D). This ensures the filling of thereactive gas 7. Then, the bronchus or bronchiole 2 is closed by usingthe means 8 for closing the bronchus or bronchiole (FIG. 2D). Closingthe bronchus or bronchiole 2 in this way allows the reactive gas 7 toenter sufficiently into the alveolar parenchyma 3 suffering fromemphysema, so that the reactive gas 7 reacts efficiently with thefilm-forming agent 3 in the film 5. Further, the gas absorbing agent 9that absorbs the reactive gas is injected into the pulmonary alveoli oralveolar sacs (the alveolar parenchyma suffering from emphysema) 3 (FIG.2E). Absorption of the reactive gas by the gas absorbing agent 9 causesthe alveolar parenchyma suffering from emphysema to aggregate, and thealveolar parenchyma suffering from emphysema decreases in volume (FIG.2F). An efficient and rapid decrease in the volume of the alveolarparenchyma can be achieved because the film 5 that suppresses andprevents air leakage has been formed in the alveolar parenchymasuffering from emphysema by the foregoing step (b). Incidentally, thegas absorbing agent 9 may be removed by suction. However, the gasabsorbing agent is not always necessarily removed as shown in FIG. 2Fbecause the shrunk alveolar parenchyma does not function as thepulmonary alveoli or alveolar sac.

The reactive gas 7 is not specifically restricted but should preferablybe one which is reactive with the film-forming agent 3 in the filmformed by the step (b). In this case, the reactive gas 7 reacts with thefilm-forming agent 3 in the film formed by the step (b), therebyallowing curing to proceed slowly and terminate after the alveolarparenchyma suffering from emphysema has shrunk. This permits thealveolar parenchyma suffering from emphysema to maintain its reducedlung volume. The reactive gas used for this purpose includes oxygen andcarbon dioxide. The above-mentioned reactive gas may be used in the formof a single gas or a mixture of gases. A preferable reactive gas isoxygen, which naturally exists in the lung and is safe even though it istaken into the body.

The reactive gas may be introduced into the alveolar parenchymasuffering from emphysema in any amount which is sufficient to fill it,and not specifically restricted. For example, injection of the reactivegas should be suspended when an increase in the injection pressure ofthe reactive gas is detected. Introduction of the reactive gas into thealveolar parenchyma suffering from emphysema may be accomplished byusing the lumen of the catheter which is identical with or differentfrom the one used for introduction of the film-forming agent.

The reactive gas introduced into the alveolar parenchyma suffering fromemphysema may rem there for any length of time, preferably 1 to 10minutes, which is enough for the reactive gas to completely react withthe film-forming agent in the film.

The means to close the bronchus or bronchiole (closing means) 8 is notspecifically restricted so long as it is capable of closing temporarilyor permanently. The temporal closing means is not specificallyrestricted and temporary closing may be accomplished by means of theballoon 1 a attached to the catheter 1, as shown in FIG. 2D. If theballoon 1 a is expanded when the reactive gas 7 is filled, the bronchusor bronchiole 2 should be kept closed after the reactive gas 7 has beenfilled. The permanent closing means is also not specifically restrictedand permanent closing may be accomplished by using a soft material likesponge for closing the bronchus or bronchiole 2. Closing in this manneralleviates and prevents the reactive gas 7 from leaking from thealveolar parenchyma 3 suffering from emphysema, thereby permittingefficient reaction between the reactive gas 7 and the film-forming agent3. The closing means 8 may be placed at any position, which is close tothe end of the catheter or at the bronchus (proximal side). If the endof the catheter is in the bronchus, the catheter should be positionedsuch that the closing means does not go beyond the branch of thebronchus on the proximal side. This prevents the reactive gas fromflowing into the bronchus on the proximal side. Incidentally, it ispermissible to previously close the bronchus or bronchiole 2 beforeintroduction of the reactive gas. This alleviates and prevents thereactive gas from flowing backward into the trachea (proximal side) ofthe bronchus or bronchiole 2, thereby permitting efficient introductionof the reactive gas into the aimed alveolar parenchyma suffering fromemphysema. The means to close the bronchus or bronchiole is notspecifically restricted, for example, the same one as the closing means8 mentioned above may be used.

The gas-absorbing agent 9 is not specifically restricted so long as itis capable of absorbing the reactive gas 7. It is selected from thefollowing examples according to the kind of the reactive gas 7. Silica,ceramics, porous ceramics, magnesia, titania, calcium silicate,activated carbon; iron powders such as pure iron powder, cast ironpowder, steel powder, reduced iron powder, sprayed iron powder, spongyiron powder, electrolytic iron powder, and iron alloy powder, aluminumpowder, magnesium powder, silicon fine powder; L-ascorbic acid,isoascorbic acid (erythorbic acid), alkali metal salt thereof, andalkaline earth metal salt thereof; polyhydric alcohols such as glycerin,ethylene glycol, and propylene glycol; phenol compounds such ascatechol, resorcin, hydroquinone, gallic acid, pyrogallol, andtocopherol; and reducing sugars such as glucose, fructose, sorbitol, andxylose. They may be used alone or in combination with one another.Preferable among the foregoing examples are iron powder, ceramics, andporous ceramics, which are safe to use.

Iron powder as one of the above-mentioned gas-absorbing agents shouldpreferably be used in combination with a pro-oxidant for better oxygenabsorption. The pro-oxidant may be selected unrestrictedly from halidesof alkali metal or alkaline earth metal such as NaCl, CaCl₂, and MgCl₂,halides of ion-exchange resin, hydrochloric acid, and hypochlorite. Thepro-oxidant should preferably be used in an amount of 0.01 to 20 partsby weight for 100 parts by weight of iron powder.

The gas-absorbing agent should be introduced into the alveolarparenchyma affected with emphysema in any unrestricted amount enough toreduce the volume of the alveolar parenchyma affected with emphysemawhich has sufficiently absorbed the reactive gas. An adequate amount isdetermined according to the volume of the alveolar parenchyma affectedwith emphysema. Alternatively, injection of the gas-absorbing agent maybe suspended as soon as an increase in injection pressure of thegas-absorbing agent is detected. Introduction of the gas-absorbing agentinto the alveolar parenchyma affected with emphysema may be carried outthrough the lumen of the catheter which is identical with the one usedfor introduction of the film-forming agent or reactive gas or differentfrom the one used for introduction of the film-forming agent or reactivegas.

The gas-absorbing agent which has been introduced into the alveolarparenchyma affected with emphysema should remain there for anunrestricted length of time, preferably ranging from 1 to 10 minutes,which is enough for the gas-absorbing agent to sufficiently absorb thereactive gas to reduce the volume of the alveolar parenchyma affectedwith emphysema.

3-2. Step (c-2)

This step employs a film-forming agent which forms a foam-like film.Following the step (b) mentioned above, the foam-like film-forming agent14 remaining uncured has its foaming gas released from the body orabsorbed into the body, so that the alveolar parenchyma 3 affected withemphysema decreases in volume as foams disappear. In this case, the stepshown in FIG. 3D is skipped from the step of FIG. 3C to the step of FIG.3E (FIG. 3C→FIG. 3E). The foam-like film-forming agent is produced fromthe film-forming agent used in the step (b) mentioned above,particularly the material 14 used in the step (b-2) mentioned abovewhich cures upon reaction with water or divalent metal ions, byincorporation with any gas of nitrogen, helium, argon, carbon monoxide,carbon dioxide, and oxygen, as a foaming agent, and foaming. Thefoam-like film-forming agent may also be produced by incorporating thefilm-forming agent with sodium hydrogen carbonate and citric acid inpowder form dispersed therein. The foregoing is a mere example of themethod for production of the foam-like film-forming agent.

Foams that occur while the foam-like film-forming agent 14 has not yetcured may be allowed to disappear naturally or forced to disappear withthe help of a defoaming agent. Foams that occur after the foam-likefilm-forming agent has cured should preferably be allowed to disappearnaturally by dif fusion. The defoaming agent used for the latter purposemay be selected unrestrictedly from defoaming agents used in the medicalfield such as lower alcohols such as methanol, ethanol, isopropanol, andbutanol; silicone compounds such as silicone oil; and organic polarcompounds such as 2-ethylhexanol, diisobutylcarbinol, amyl alcohol,tributyl phosphate, octylphosphate sodium, metal salt of stearic acid,metal salt of palmitic acid, isoamyl stearate, diglycol laurate,sorbitan trioleate, polyoxyethylene sorbitanmonolaurate, Pluronicnonionic surfactant, polyalkylene glycol and derivatives thereof. Thesedefoaming agents may be used alone or in combination with one another.Preferable among these defoaming agents are derivatives of polyalkyleneglycol, which excel in defoaming performance. The defoaming agent shouldbe introduced into the alveolar parenchyma affected with emphysema in anamount sufficient to defoam the uncured foam-like film-forming agent tosuch an extent as required to sufficiently reduce the volume of thealveolar parenchyma affected with emphysema. The amount of the defoamingagent should preferably be about 0.001 to 5 wt % of the amount of theinitially introduced foam-like film-forming agent. Introduction of thedefoaming agent into the alveolar parenchyma affected with emphysema maybe carried out through the lumen of the catheter which is identical withthe one used for introduction of the film-forming agent or differentfrom the one used for introduction of the film-forming agent.

The foam-like film-forming agent 14 remaining uncured may be removed bysuction through the catheter 1, so that the volume of the alveolarparenchyma 3 affected with emphysema is reduced. In this case, the stepof FIG. 3C continues to the step of FIG. 3E through the step of FIG. 3D(FIG. 3C→FIG. 3D→FIG. 3E). The foam-like film-forming agent 14 remaininguncured should be removed in any amount substantially available for thealveolar parenchyma affected with emphysema. It may be sucked out untilsuction of the foam-like film-forming agent becomes impossible tocontinue. Introduction and removal of the foam-like film-forming agentmay be carried out through the lumen of the catheter which is identicalwith the one used for introduction of the film-forming agent ordifferent from the one used for introduction of the film-forming agent.

3-3. Step (c-3)

This step is intended to remove by suction through the catheter any gasremaining in the pulmonary alveoli or alveolar sacs (FIG. 4F). There mayexist an instance in which the alveolar parenchyma 3 affected withemphysema remains expanded even after the film-forming agent has beenremoved by suction. In this case, residual gas in the alveolarparenchyma 3 affected with emphysema should be removed by suctionthrough the catheter, so that the volume of the alveolar parenchymaaffected with emphysema is reduced efficiently and rapidly because thealveolar parenchyma 3 affected with emphysema is closed except for holescommunicating with the bronchus or bronchiole 2. Removal by suction ofresidual gas from the alveolar parenchyma 3 affected with emphysemashould be continued until suction becomes impossible to continue.

3-4. Step (c-4)

This step is intended to remove by suction the film-forming agent fromthe pulmonary alveoli or alveolar sacs. Since the alveolar parenchymaaffected with emphysema is closed except for holes communicating withthe bronchus or bronchiole as mentioned above, the alveolar parenchyma 3shrinks according as the film-forming agent is removed by suction. Thisstep is very simple and hence desirable. If the alveolar parenchyma 3does not shrink sufficiently even after this step, it is desirable toperform at least one of the above-mentioned steps (c-1) to (c-3).

The foregoing is a detailed description of the step (a), the steps (b-1)to (b-3), and the steps (c-1) to (c-3). These steps may be employed inany combination. Examples of the desirable combination are as follows.

Steps (a) and (b-1); steps (a) and (b-2); steps (a) and (b-3); steps(a), (b-1), and (c-1); steps (a), (b-1), and (c-3); steps (a), (b-2),and (c-2); and steps (a), (b-3), and (c-3). Examples of the moredesirable combination are as follows. Steps (a) and (b-1); steps (a) and(b-2); steps (a) and (b-3); steps (a), (b-1), and (c-1); steps (a),(b-2), and (c-2); and steps (a), (b-3), and (c-3).

As mentioned above, the method for treatment according to the presentinvention is designed to efficiently remove air remaining in thealveolar parenchyma affected with emphysema, thereby maintaining thevolume reduced by respiration. Therefore, it enables one to alleviateand prevent over-expansion of the lung which weakens the patient byemphysema or occlusion of air-supply bronchi. In addition, it permitsthe alveolar parenchyma affected with emphysema to become smaller thanits original size, with the neighboring bronchi being alleviated andprevented from pressure or occlusion by their surrounding alveolarparenchyma. Moreover, the method for treatment according to the presentinvention relieves the patient from burden because it relies onoperation through the catheter without surgical operation. The presentinvention produces additional effects of forming the film on the innerwall of the alveolar parenchyma affected with emphysema, therebyrestoring the elasticity of the alveolar parenchyma affected withemphysema and alleviating and preventing the over-expansion of the lung.

EXAMPLES

The present invention will be described below in more detail withreference to the following examples which demonstrate the method fortransbronchially coating the tissue of the alveolar sac (air sac) orpulmonary alveoli, the tissue of the terminal bronchiole, and the tissueof the bypass which exist at arbitrary positions. The examples are notintended to restrict the scope of the present invention.

Example 1

The first step started with insertion of a balloon catheter 1 into thelumen of the bronchiole 2 as shown in FIG. 2A through the working lumenof the bronchoscope (not shown). This balloon catheter is PTCA ballooncatheter of OTW type (Ryujin Plus OTW (registered trademark), MedicalInstrument Approval Number 21600BZZ00035, made by TERUMO CORPORATION)which is designed for treatment of angiostenosis of the vascular lumenin the cardiovascular region. The working lumen of the bronchoscope hasa guide wire with an outside diameter of 0.014 inches (Runthrough(registered trademark), made by TERUMO CORPORATION) which was previouslyinserted therein. The tip of this guide wire was advanced to thevicinity of the intended alveolar parenchyma 3 affected with emphysemawith the help of X ray fluoroscopy. Then, the catheter was advancedalong the guide wire to the vicinity of the intended alveolar parenchyma3 affected with emphysema with the help of X ray fluoroscopy. Finally,the guide wire was pulled out.

As shown in FIG. 2B, an aqueous solution (2 wt %) of gelatin was filledinto a syringe as the film-forming agent 4. The balloon 1 a was expandedwith air by means of a syringe connected to the lumen for balloonexpansion arranged at the base end of the catheter 1, so that thebronchiole 2 was closed. The aqueous solution of gelatin was injectedinto the lumen of the alveolar parenchyma 3 affected with emphysemathrough the lumen of the catheter 1. Injection of the aqueous solutionof gelatin was suspended when the injection pressure of the syringeincreased. In this way, a sufficient amount of the gelatin aqueoussolution was injected into the lumen of the alveolar parenchyma 3. Thethus injected aqueous solution of gelatin was allowed to stand for fiveminutes, so that the gelatin cured. The gelatin aqueous solution 4 wasremoved by suction. That portion of the gelatin aqueous solution 4 whichremained uncured was removed by suction efficiently because the bypass 6was closed by the film 5 of gelatin which was formed on the inner wallof the alveolar parenchyma 3 affected with emphysema (FIG. 2C).

The balloon 1 a of the catheter 1 was expanded with air in the same wayas mentioned above, so that the bronchiole 2 was closed, and then oxygenas the reactive gas 7 was injected through the inflation lumen, as shownin FIG. 2D. The reactive gas 7 was filled efficiently into the alveolarparenchyma 3 because the lumen of the alveolar parenchyma 3 was coatedwith the film-forming agent 4.

Iron powder as the gas-absorbing agent 9 was sprayed into the lumen ofthe alveolar parenchyma 3 affected with emphysema through the lumenwhich capable of gas delivery of the catheter 1, as shown in FIG. 2E.The amount of the sprayed iron powder was about 3.2 mg per 1 mL of thevolume of the lumen of the alveolar parenchyma 3. The sprayed ironpowder absorbed the gas remaining in the alveolar parenchyma 3 affectedwith emphysema, thereby shrinking the alveolar parenchyma 3 affectedwith emphysema and reducing the volume thereof (FIG. 2F). It was alsoconfirmed that the alveolar parenchyma 3 affected with emphysema keptits reduced volume because the gelatin continued to cure with thereduced volume maintained (FIG. 2F).

Example 2

The first step started with insertion of a balloon catheter 1 into thelumen of the bronchiole 2 (as shown in FIG. 3A) through the workinglumen of the bronchoscope (not shown). This balloon catheter 1 is PTCAballoon catheter of OTW type (Ryuj in Plus OTW (registered trademark),Medical Instrument Approval Number 21600BZZ00035, made by TERUMOCORPORATION) which is designed for treatment of angiostenosis of thevascular lumen in the cardiovascular region. The working lumen of thebronchoscope has a guide wire with an outside diameter of 0.014 inches(Runthrough (registered trademark), made by TERUMO CORPORATION) whichwas previously inserted therein. The tip of this guide wire was advancedto the vicinity of the intended alveolar parenchyma 3 affected withemphysema with the help of X ray fluoroscopy. Then, the catheter wasadvanced along the guide wire to the vicinity of the intended alveolarparenchyma 3 affected with emphysema with the help of X ray fluoroscopy.Finally, the guide wire was pulled out.

As shown in FIG. 3B, octyl-α-cyanoacrylate prepared from sodium hydrogencarbonate and citric acid, both dispersed therein in powder form wasfilled into a syringe as the foam-like film-forming agent 14. At thetime, low-molecular-weight polyethylene glycol was added thereinto toreduce viscosity of the solution of octyl-α-cyanoacrylate. The balloon 1a was expanded with air by means of the indeflator connected to thelumen for balloon expansion arranged at the base end of the catheter 1,so that the bronchiole 2 was closed. The octyl-α-cyanoacrylate wasinjected into the lumen of the alveolar parenchyma 3 affected withemphysema through the lumen of the catheter 1 from the syringe.Injection of the octyl-α-cyanoacrylate was suspended when the injectionpressure of the syringe increased. In this way, a sufficient amount ofoctyl-α-cyanoacrylate was injected into the lumen of the alveolarparenchyma 3. The thus injected octyl-α-cyanoacrylate rapidly cured uponreaction with water 15 present on the surface of the alveolar parenchyma3 affected with emphysema, thereby forming the film 16 on the inner wallof the alveolar parenchyma 3 (FIG. 3C). At the same time, it gave riseto foams of carbon dioxide gas.

The reaction of octyl-α-cyanoacrylate with water 15 present on thesurface of the alveolar parenchyma 3 affected with emphysema wasobserved by adding water dropwise to octyl-α-cyanoacrylate placed on aslide glass simultaneously with the start of injection of theoctyl-α-cyanoacrylate. After complete film formation was confirmed, theoctyl-α-cyanoacrylate was removed by suction (FIG. 3D). It was possibleto efficiently remove by suction the octyl-α-cyanoacrylate 14 remainingunreacted because the bypass 6 was closed by the film formation.

It was confirmed that the volume of the alveolar parenchyma 3 affectedwith emphysema decreased as the octyl-α-cyanoacrylate was removed bysuction and the carbon dioxide foams that occurred in theoctyl-α-cyanoacrylate disappeared. It was also confirmed that thealveolar parenchyma 3 affected with emphysema kept its reduced volumebecause the octyl-α-cyanoacrylate continued to cure with the reducedvolume maintained (FIG. 3E).

Example 3

As shown in FIG. 3A, the first step started with insertion of a ballooncatheter 1 into the lumen of the bronchiole 2 through the working lumenof the bronchoscope (not shown). This balloon catheter 1 is PTCA ballooncatheter of OTW type (Ryuj in Plus OTW (registered trademark), MedicalInstrument Approval Number 21600BZZ00035, made by TERUMO CORPORATION)which is designed for treatment of angiostenosis of the vascular lumenin the cardiovascular region. The working lumen of the bronchoscope hasa guide wire with an outside diameter of 0.014 inches (Runthrough(registered trademark), made by TERUMO CORPORATION) which was previouslyinserted therein. The tip of this guide wire was advanced to thevicinity of the intended alveolar parenchyma 3 affected with emphysemawith the help of X ray fluoroscopy. Then, the catheter was advancedalong the guide wire to the vicinity of the intended alveolar parenchyma3 affected with emphysema with the help of X ray fluoroscopy. Finally,the guide wire was pulled out.

As shown in FIG. 3B, an aqueous solution (10 wt %) of alginic acidincorporated with carbon dioxide was filled into a syringe as thefoam-like film-forming agent 14. Carbon dioxide foams were made bydissolving sodium hydrogen carbonate into the aqueous solution ofalginic acid and then adding dilute hydrochloric acid thereinto. Theballoon 1 a was expanded with air by means of the indeflator connectedto the lumen for balloon expansion arranged at the base end of thecatheter 1, so that the bronchiole 2 was closed. The aqueous solution ofalginic acid was injected into the lumen of the alveolar parenchyma 3affected with emphysema through the lumen of the catheter 1 from thesyringe. Injection of the aqueous solution of alginic acid was suspendedwhen the injection pressure of the syringe increased. In this way, theaqueous solution of alginic acid was sufficiently injected into thelumen of the alveolar parenchyma 3. The thus injected alginic acidrapidly cured upon reaction with calcium ions 15 present on the surfaceof the alveolar parenchyma 3 affected with emphysema, thereby formingthe film 16 on the inner wall of the alveolar parenchyma 3 (FIG. 3C).

Injection of the aqueous solution of alginic acid was followed bystanding for three minutes during which the film formed. After that, theaqueous solution of alginic acid was removed by suction (FIG. 3D). Itwas possible to efficiently remove by suction the aqueous solution ofalginic acid 14 remaining unreacted because the bypass 6 was closed bythe film formation.

It was confirmed that the volume of the alveolar parenchyma 3 affectedwith emphysema decreased as the aqueous solution of alginic acid wasremoved by suction and the carbon dioxide foams that occurred in theaqueous solution of alginic acid disappeared. As an excess of theaqueous solution of alginic acid is removed by suction, theconcentration of calcium ions increased on the surface 15 of thealveolar parenchyma 3 affected with emphysema. The result was thatreaction between alginic acid 14 and calcium ions 15 proceededeffectively on the surface of the alveolar parenchyma 3 affected withemphysema to form the film, and the alveolar parenchyma 3 affected withemphysema maintained its reduced volume (FIG. 3E).

Example 4

The first step started with insertion of a balloon catheter 1 into thelumen of the bronchiole 2 (as shown in FIG. 4A) through the workinglumen of the bronchoscope (not shown). This balloon catheter 1 is PTCAballoon catheter of OTW type (Ryuj in Plus OTW (registered trademark),Medical Instrument Approval Number: 21600BZZ00035, made by TERUMOCORPORATION) which is designed for treatment of angiostenosis of thevascular lumen in the cardiovascular region. The working lumen of thebronchoscope has a guide wire (Runthrough (registered trademark), madeby TERUMO CORPORATION) (outside diameter: 0.014 inches) which waspreviously inserted in the working lumen of the bronchoscope. The tip ofthis guide wire was advanced to the vicinity of the aimed alveolarparenchyma 3 affected with emphysema with the help of X ray fluoroscopy.Then, the catheter was advanced along the guide wire to the vicinity ofthe aimed alveolar parenchyma 3 affected with emphysema with the help ofX ray fluoroscopy. Finally, the guide wire was pulled out.

As shown in FIG. 4B, the balloon 1 a was expanded with air by means ofthe indeflator connected to the lumen for balloon expansion arranged atthe base end of the catheter 1, so that the bronchiole 2 was closed.Hyaluronic acid as the polymeric electrolyte (A) 24, which hadpreviously been filled into a syringe, was injected into the lumen ofthe alveolar parenchyma 3 affected with emphysema through the lumen ofthe catheter 1 from the syringe. Injection of the hyaluronic acid wassuspended when the injection pressure of the syringe increased. Next, anexcess amount of the hyaluronic acid was removed by suction. The stepsfor injection and removal of hyaluronic acid were repeated severaltimes. Then, the balloon 1 a, which had kept closed the bronchiole 2,was shrunk so that the bronchiole 2 had communications with the outside.This step formed the coating film 25 of hyaluronic acid as the polymericelectrolyte (A) 24 on the surface of the tissue of the alveolarparenchyma 3 affected with emphysema. (FIG. 4C)

Next, as shown in FIG. 4D, the balloon 1 a was expanded again with airby means of the indeflator connected to the lumen for balloon expansionarranged at the base end of the catheter 1, so that the bronchiole 2 wasclosed. Poly(N,N-dimethylaminopropylacrylamide) (having aweight-average-molecular weight of 10,000 to 500,000) was filled in theother syringe as the polymeric electrolyte (B) 26. Thepoly(N,N-dimethylaminopropylacrylamide) was injected into the lumen ofthe alveolar parenchyma suffering from emphysema using a syringe throughthe other lumen which are different from those used for injection ofhyaluronic acid of the catheter 1. Injection of thepoly(N,N-dimethylaminopropylacrylamide) was suspended when the injectionpressures of the syringe increased. Thepoly(N,N-dimethylaminopropylacrylamide), which has been injected intothe lumen of the alveolar parenchyma 3, rapidly reacted for curing withthe hyaluronic acid which had previously formed the film 25 on thesurface of the tissue of the alveolar parenchyma 3 suffering fromemphysema (FIG. 4D).

After injection, the poly(N,N-dimethylaminopropylacrylamide) was allowedto stand for five minutes for reacting sufficiently with the hyaluronicacid, thereby forming the ion complex film 27, and then the excessportion of the poly(N,N-dimethylaminopropylacrylamide) was removed bysuction. After that, air which has lower viscosity than the hyaluronicacid and poly(N,N-dimethylaminopropylacrylamide) was injected from theforward end of the catheter 1 so that the polymeric electrolyte (B) 26formed a uniform film on the surface of the alveolar parenchyma 3suffering from emphysema (FIG. 4E).

The alveolar parenchyma 3 suffering from emphysema was evacuated bysuction through the catheter 1 so that the volume of the alveolarparenchyma 3 suffering from emphysema was decreased. At this time, thedecreased volume of the alveolar parenchyma 3 suffering from emphysemawas maintained for a long period of time as the reaction betweenhyaluronic acid and poly(N,N-dimethylaminopropylacrylamide) proceededand the cross-linking reaction in the ion complex film proceededaccordingly (FIG. 4F).

The invention claimed is:
 1. A method for treatment of emphysema in apatient in need thereof, comprising: (a) inserting a catheter into abronchus or bronchiole of the patient to reach a respiratory regioncomprising pulmonary alveoli or alveolar sacs, the respiratory regionincluding an inner wall; (b(i)) injecting air into the respiratoryregion through the catheter at an air injection pressure; (b(ii))injecting a film-forming agent into the respiratory region through thecatheter while maintaining the air injection pressure, thereby forming afilm on the inner wall of the respiratory region, wherein step (b(ii))comprises (b-1) injecting the film-forming agent, which is a viscouspolymer solution, into the respiratory region through the catheter andthen removing by suction an excess of the viscous polymer solution;(b-2) injecting the film-forming agent, which is a material capable ofcuring upon reaction with water or divalent metal ions, into therespiratory region through the catheter, allowing the material to reactwith water or divalent metal ions present on the surface of therespiratory region, and then removing by suction an excess of thematerial; or (b-3) injecting a first polymeric electrolyte having acharge into the respiratory region through the catheter and thenremoving by suction an excess of the first polymeric electrolyte,thereby allowing the first polymeric electrolyte to form a coating filmon the inner wall of the respiratory region, and then injecting a secondpolymeric electrolyte, which has a charge opposite to the charge of thefirst polymeric electrolyte, into the respiratory region through thecatheter, thereby allowing the second polymeric electrolyte to contactthe coating film of the first polymeric electrolyte, and then removingby suction an excess of electrolyte, and finally removing by suction anexcess of the first polymeric electrolyte, with the first polymericelectrolyte and the second polymeric electrolyte serving as thefilm-forming agent and (c) shrinking the pulmonary alveoli or alveolarsacs.
 2. The method of claim 1, wherein the catheter has a balloon, andstep (b(i)) further includes an additional substep of closing thebronchus or bronchiole by expanding the balloon attached to the catheterprior to injection of the film-forming agent.
 3. The method of claim 2,wherein the step (b(ii)) comprises the steps of (b-3), and furthercomprising, after removal by suction of the excess of the secondpolymeric electrolyte, injecting the first polymeric electrolyte intothe respiratory region through the catheter, and finally removing bysuction an excess of the first polymeric electrolyte, with the firstpolymeric electrolyte and the second polymeric electrolyte serving asthe film-forming agent.
 4. The method of claim 3, wherein the step (c)for shrinking the pulmonary alveoli or alveolar sacs is carried out byany of: (c-1) filling a reactive gas into the pulmonary alveoli oralveolar sacs through the catheter, and then closing the bronchus orbronchiole by a means to close a bronchus or bronchiole and injecting agas absorbing agent that absorbs the reactive gas into the pulmonaryalveoli or alveolar sacs; (c-2) after the step (b) in which thefilm-forming agent is one capable of forming a foam-like film, thenallowing the foams of the film-forming agent to disappear or removing bysuction the foam-like film-forming agent through the catheter; or (c-3)removing by suction residual gas from the pulmonary alveoli or alveolarsacs through the catheter.
 5. The method of claim 1, wherein thecatheter has a balloon in the center side, and the injection of thefilm-forming agent is at a constant pressure and is preceded byinjecting air through the catheter into the respiratory region whilemaintaining a constant pressure.
 6. The method of claim 1, wherein thestep (c) for shrinking the pulmonary alveoli or alveolar sacs is carriedout by any of: (c-1) filling a reactive gas into the pulmonary alveolior alveolar sacs through the catheter, and then closing the bronchus orbronchiole by a means to close a bronchus or bronchiole and injecting agas absorbing agent that absorbs the reactive gas into the pulmonaryalveoli or alveolar sacs; (c-2) after the step (b) in which thefilm-forming agent is one capable of forming a foam-like film, thenallowing the foams of the film-forming agent to disappear or removing bysuction the foam-like film-forming agent through the catheter; (c-3)removing by suction residual gas from the pulmonary alveoli or alveolarsacs through the catheter; or (c-4) removing by suction the film-formingagent through the catheter.
 7. The method of claim 1, wherein the step(c) for shrinking the pulmonary alveoli or alveolar sacs is carried outby any of the steps (b-1) to (b-3) and optionally by any of: (c-1)filling a reactive gas into the pulmonary alveoli or alveolar sacsthrough the catheter, and then closing the bronchus or bronchiole by ameans to close a bronchus or bronchiole and injecting a gas absorbingagent that absorbs the reactive gas into the pulmonary alveoli oralveolar sacs; (c-2) after the step (b) in which the film-forming agentis one capable of forming a foam-like film, then allowing the foams ofthe film-forming agent to disappear or removing by suction the foam-likefilm-forming agent through the catheter; or (c-3) removing by suctionresidual gas from the pulmonary alveoli or alveolar sacs through thecatheter.